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==Introduction==
==Introduction==
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Ciliary Neurotrophic Factor (CNTF) is a nerve growth factor belonging to the Interleukin-6 (IL-6)
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[[Image:CNTF_cropped.png|300px|left|thumb| Ciliary neurotrophic factor, [[1cnt]]]]
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Human Ciliary Neurotrophic Factor (CNTF) is a roughly 23 kDa protein consisting of a single
 +
polypeptide chain of 200 amino acid residues. It is a nerve growth factor belonging to the Interleukin-6 (IL-6)
family of neuropoietic cytokines.
family of neuropoietic cytokines.
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Other members of this family include leukemia inhibitory factor (LIF), IL-6, IL-11 and
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Other members of this family include leukemia inhibitory factor (LIF), IL-6, IL-11,
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oncostatin M (Wang 2012).
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oncostatin M, cardiotropin 1 (CT-1) and cardiotrophin-like cytokine (CLC) <ref name="Wen2012">PMID: 22182585</ref>.
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<StructureSection load='1CNT_trunc.pdb' size='500' frame='true' side='right' caption='Dimeric structure of CNTF in 2.4 Å resolution' scene='57/579704/Dimer_basic_view/3' >
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==Receptor for CNTF and the biological role of CNTF==
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[[Image:CNTF_receptorbinding.png|280px|right|thumb| Binding of CNTF to the high affinity receptor complexes CNTFRα/gp130/LIFRβ and to the low affinity receptor complex IL-6R/gp130/LIFRβ (modified from <ref name="Wen2012" /> <ref name="Li2011"> doi:10.1371/journal.pone.0023148 </ref>)]]
CNTF exerts its biological function by binding into a tripartite
CNTF exerts its biological function by binding into a tripartite
receptor complex consisting of a specific CNTF receptor subunit α (CNTFRα) linked to
receptor complex consisting of a specific CNTF receptor subunit α (CNTFRα) linked to
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signal transduction cascade, which ultimately results in the enhanced transcription
signal transduction cascade, which ultimately results in the enhanced transcription
of genes encoding e.g. acute phase plasma proteins, and suppressors of cytokine signaling.
of genes encoding e.g. acute phase plasma proteins, and suppressors of cytokine signaling.
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CNTFRα has been observed to exist also as a soluble receptor (sCNTFRα) (Panayotatos ''et al.'' 1994), attributed
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CNTFRα has been observed to exist also as a soluble receptor (sCNTFRα) <ref name="Panayotatos1994">PMID: 8180210</ref>, attributed
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to a phospholipase C-mediated cleavage (Davis ''et al.'' 1993).
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to a phospholipase C-mediated cleavage <ref name="Davis1993"> PMID: 7681218</ref>.
Additionally, hCNTF has been observed to be
Additionally, hCNTF has been observed to be
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able to bind to Interleukin-6 receptor (IL-6R) and use as a substitute it to form the receptor complex
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able to bind both to membrane-bound and soluble human Interleukin-6 receptor (IL-6R) and use as a substitute it to form the receptor complex
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necessary for signal transduction (Schuster ''et al.'' 2003, Cognet ''et al.'' 2004). These observaations are considered to
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necessary for signal transduction <ref name="Schuster2003"> PMID: 12643274 </ref> <ref name="Cognet2004">PMID: 15542451</ref>. These observations are considered to
offer explanation as to why cells expressing LIFRβ and gp130
offer explanation as to why cells expressing LIFRβ and gp130
but not CNTFRα, are nonetheless responsive to CNTF.
but not CNTFRα, are nonetheless responsive to CNTF.
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CNTF's known biological functions involve affecting the growth, differentiation, survival and repair
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CNTF's known biological functions involve affecting the growth, differentiation, survival and repair of various types of neurons and glial cells in both the central and peripheral nervous systems <ref name="Sleeman2000">Sleeman MW, Anderson KD, Lambert PD, Yancopoulos GD and Wiegand SJ. "The ciliary neurotrophic factor and its receptor, CNTFRα". Pharm Acta Helv 74: 265-272 (2000). http://dx.doi.org/10.1016/S0165-7208(00)80028-8</ref> <ref name="Cognet2004" />; evidence also suggests CNTF to be expressed in other tissues, such as adipocytes and hepatocytes among others <ref name="Sleeman2000" /> <ref name="Cognet2004" />.
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of various types of neurons and glial cells in both the central and peripheral nervous
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systems (Sleeman ''et al.'' 2000, Cognet ''et al.'' 2004); evidence also suggests CNTF to
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be expressed in other tissues, such as adipocytes and hepatocytes among others ().
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As the transcription of CNTF mRNA and CNTF distribution have been noticed to be altered upon neural injury,
As the transcription of CNTF mRNA and CNTF distribution have been noticed to be altered upon neural injury,
it has been suggested, that CNTF is not an absolute requirement for neural
it has been suggested, that CNTF is not an absolute requirement for neural
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Furthermore, mice homozygous for an inactived CNTF gene have been observed to develop normally, and to display losses
Furthermore, mice homozygous for an inactived CNTF gene have been observed to develop normally, and to display losses
in motor neurons only later during adulthood. Although humans homozygous for an inactivated CNTF gene
in motor neurons only later during adulthood. Although humans homozygous for an inactivated CNTF gene
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caused by a mutation have not been observed to suffer from major neurological abnormalities (Wang 2012),
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caused by a mutation have not been observed to suffer from major neurological abnormalities <ref name="Wen2012" />,
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this has been linked with early onset of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) (Cognet ''et al.'' 2004).
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this has been linked with early onset of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) <ref name="Cognet2004" />.
However, mice that have a CNTFRα knock-out die already during the perinatal stage and exhibit severe motor
However, mice that have a CNTFRα knock-out die already during the perinatal stage and exhibit severe motor
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neuron deficits (Sleeman ''et al.'' 2000), suggesting that CNTFRα might have a second ligand.
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neuron deficits <ref name="Sleeman2000" />, suggesting that CNTFRα might have a second ligand.
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==Disease and Clinical applications==
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A frameshift mutation in exon 2 of the CNTF gene affecting some 2-3 % of the population <ref name="Takahashi1994">PMID: 8075647 </ref> causes earlier onset of the disease and quicker declination of motor neuron function in MS patients <ref name="Giess2002">PMID: 11890844 </ref>.
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MS patients with functional CNTF show 1,7-fold increase of CNTF mRNA expression in the cortex, suggesting CNTF secretion as an innate response to progressing neuronal damage <ref name="Dutta2007">PMID: 17898009 </ref>.
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While not directly linked to disease, CNTF has been shown to inhibit the secretion of vascular endothelial growth factor (VEGF). VEGF, in turn, is upregulated in many diseases of the retina, causing increased angiogenesis. Thus CNTF-induced downregulation alleviates the symptoms of many ocular diseases <ref name="Li2011" />. It has been proposed that treatment with CNTF could counteract vision loss caused by age-related macular degeneration, retinitis pigmentosa and retinitis pigmentosa linked to Usher syndrome. In these cases the alleviating effect is produced by CNTF inducing regeneration of outer segments of cone cells in the retina <ref name=Li2010> PMID: 20209167 </ref>. Using encapsulated cells transfected with the human CNTF gene has been studied as a delivery method in clinical studies<ref name="Sieving"> doi: 10.1073/pnas.0600236103 </ref>, <ref name=Talcott2011> PMID: 21087953 </ref>.
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As CNTF has also been shown to affect energy balance, it also has potential clinical applications in the prevention and treatment of obesity and type II diabetes <ref name="Sleeman2000" /> <ref name="Ettinger2003"> PMID: 12684362 </ref>.
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==Structure==
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Like with many other cytokines, the tertiary structure of CNTF consists of four anti-parallel α-helices <scene name='57/579704/A-helix/4'>A</scene> (Arg<sup>13</sup>–His<sup>41</sup>), <scene name='57/579704/B-helix/2'>B</scene> (Glu<sup>69</sup>–Val<sup>96</sup>), <scene name='57/579704/C-helix/2'>C</scene> (Phe<sup>105</sup>–Leu<sup>129</sup>) and <scene name='57/579704/D-helix/2'>D</scene> (Phe<sup>152</sup>–Ser<sup>180</sup>), where helices A-B and C-D are connected
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by two cross-over loops and helices B-C by one short loop. A partial crystal structure of a truncated form of hCNTF (2-187) is displayed here <ref name="McDonald1995" />.
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The CNTFRα-binding surface epitope of CNTF was studied with random mutagenesis and identified to consist of residues Arg<sup>25</sup>, Arg<sup>28</sup>, Gln<sup>63</sup>, Trp<sup>64</sup>, Gln<sup>74</sup>, Asp<sup>175</sup> and Arg<sup>177</sup>. These residues are located in helix A, the loop between helices A-B, helix B and helix D, and are <scene name='57/579704/Cntfr_binding_epitope_spacefil/1'>spatially clustered and surface accessible</scene> <ref name=”Panayotatos1995”> PMID: 7539796 </ref>.
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In addition, the LIFR-binding epitope of CNTF was identified to consist of <scene name='57/579704/Lifr_binding_epitope/1'>amino acid chains</scene> Glu<sup>36</sup>-Met<sup>56</sup>, Leu<sup>91</sup>-Ile<sup>109</sup> and Gly<sup>147</sup>-Leu<sup>162</sup> <ref name=”Kallen1999”> PMID: 10207005</ref>. The ability of hCNTF to bind both to CNTFRα and IL-6R has been mapped to
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residue Gln<sup>63</sup> <ref name="Schuster2003" />.
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<scene name='58/584309/Cntf/1'>TextToBeDisplayed</scene>
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The dimeric structure of CNTF is attributed to the properties of hydrophobic (Leu<sup>91</sup>, Leu<sup>113</sup>, Leu<sup>114</sup>, Ala<sup>117</sup>, Tyr<sup>121</sup>, Ile<sup>128</sup>), polar (Gln<sup>95</sup>) and charged residues (Arg<sup>81</sup>, His<sup>84</sup>, Glu<sup>92</sup>, His<sup>106</sup>, His<sup>110</sup>, Glu<sup>124</sup>, Glu<sup>125</sup>) in the B and C helices of monomeric CNTF. These interface sites are highly conserved among species, except for Gln<sup>95</sup>. In the dimeric structure, <scene name='57/579704/Cntf_hbonds/3'>two water molecules are buried in the interface of the two monomers</scene>, forming hydrogen bonds to His<sup>84</sup> and Tyr<sup>121</sup> of each monomer<ref name="McDonald1995">PMID: 7796798</ref>.
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Fig. 1 X-ray structure of a truncated form of hCNTF (2-187)
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</StructureSection>
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==Structure==
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==Additional Resources==
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Overview
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CNTF is a roughly 22.7 kDa protein consisting of a single
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[http://www.rcsb.org/pdb/explore/explore.do?structureId=1CNT]
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polypeptide chain of 200 amino acid residues.
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Like with many other cytokines, the tertiary structure of CNTF
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-
consists of four anti-parallel α-helices (A-D), where helices A-B and C-D are connected
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-
by two cross-over loops and helices B-C by one short loop.
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-
 
+
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(Kallen ''et al.'' 1999) CNTF LIFR binding epitope (Glu36-Met56, Leu91-Ile109 and Gly147-Leu162)
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==Disease==
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While not directly linked to disease, CNTF has been shown to inhibit the secretion of VEGF in the human retina, alleviating the symptoms of some ocular diseases (Li 2011). It has been proposed that treatment with CNTF could counteract vision loss caused by age-related loss of vision, retinitis pigmentosa and retinitis pigmentosa linked to Usher syndrome. In these cases the alleviating effect is produced by CNTF inducing regeneration of outer segments of cone cells in the retina (Li 2010). Using capsulated cells transfected with the human CNTF gene has been studied as a delivery method (Sieving 2006, Talcott 2011).
+
-
 
+
-
A frameshift mutation in exon 2 of the CNTF gene affecting some 2-3 % of the population (Takahashi 1994) causes earlier onset of the disease and quicker declination of motor neuron function in MS patients (Giess 2002). MS patients with functional CNTF show 1,7-fold increase of CNTF mRNA expression in the cortex, suggesting CNTF secretion as an innate response to progressing neuronal damage (Duetta 2007).
+
==References==
==References==
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<references/>
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Cognet I, Guilhot F, Chevalier S, Guay-Giroux A, Bert A, Elson GCA, Gascan H and Gauchat J-F: Expression of biologically active mouse ciliary neurotrophic factor (CNTF) and soluble CNTFRα in Eschericia coli and characterization of their functional specificities. Eur Cytokine Netw 15: 255-262 (2004).
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-
 
+
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Li Y, Tao W, Luo L, Huang D, Kauper K, Stabila P, LaVail MM, Laties AM and Wen R: CNTF induces regeneration of cone outer segments in a rat model of retinal degeneration. PLoS One 5: 1-7 (2010).
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-
 
+
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Li Y, Wen R, Banzon T, Maminishkis A and Miller SS: CNTF mediates neurotrophic factor secretion and fluid absorption in human retinal pigment epithelium. PLoS One 6: 1-7 (2011).
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-
 
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McDonald NQ, Panayotatos N and Hendrickson WA: Crystal structure of dimeric human ciliary neurotrophic factor determined by MAD phasing. EMBO J 14: 2689-2699 (1995).
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-
 
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Richardson PM: Ciliary neurotrophic factor: A review. Pharmac Ther 63: 187-198 (1994).
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-
 
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Sieving PA, Caruse RC, Tao W, Coleman HR, Thompson DJS, Fullmer KR and Bush RA: Ciliary neurotrophic factor (CNTF) for human retinal degeneration: Phase I trial of CNTF delivered by encapsulated cell intraocular implants. PNAS 103: 3896-3901 (2006).
+
-
 
+
-
Sleeman MW, Anderson KD, Lambert PD, Yancopoulos GD and Wiegand SJ: The ciliary neurotrophic factor and its receptor, CNTFRα. Pharm Acta Helv 74: 265-272 (2000).
+
-
 
+
-
Wen R, Song Y, Kjellstrom S, Tanikawa A, Liu Y, Li Y, Zhao L, Bush RA, Laties AM and Sieving PA: Regulation of rod phototransduction machinery by ciliary neurotrophic factor. J Neurosci 26: 13523-13530 (2006).
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-
 
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Wen R, Tao W, Li Y and Sieving PA: CNTF and retina. Prog Retin Eye Res 31: 136-151 (2012).
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Introduction

Ciliary neurotrophic factor, 1cnt
Ciliary neurotrophic factor, 1cnt

Human Ciliary Neurotrophic Factor (CNTF) is a roughly 23 kDa protein consisting of a single polypeptide chain of 200 amino acid residues. It is a nerve growth factor belonging to the Interleukin-6 (IL-6) family of neuropoietic cytokines. Other members of this family include leukemia inhibitory factor (LIF), IL-6, IL-11, oncostatin M, cardiotropin 1 (CT-1) and cardiotrophin-like cytokine (CLC) [1].

Dimeric structure of CNTF in 2.4 Å resolution

Drag the structure with the mouse to rotate

Additional Resources

[1]

References

  1. ↑ 1.0 1.1 1.2 Wen R, Tao W, Li Y, Sieving PA. CNTF and retina. Prog Retin Eye Res. 2012 Mar;31(2):136-51. doi: 10.1016/j.preteyeres.2011.11.005., Epub 2011 Dec 10. PMID:22182585 doi:http://dx.doi.org/10.1016/j.preteyeres.2011.11.005
  2. ↑ 2.0 2.1 Li R, Wen R, Banzon T, Maminishkis A, Miller SS. CNTF mediates neurotrophic factor secretion and fluid absorption in human retinal pigment epithelium. PLoS One. 2011;6(9):e23148. doi: 10.1371/journal.pone.0023148. Epub 2011 Sep 2. PMID:21912637 doi:http://dx.doi.org/10.1371/journal.pone.0023148
  3. ↑ Panayotatos N, Everdeen D, Liten A, Somogyi R, Acheson A. Recombinant human CNTF receptor alpha: production, binding stoichiometry, and characterization of its activity as a diffusible factor. Biochemistry. 1994 May 17;33(19):5813-8. PMID:8180210
  4. ↑ Davis S, Aldrich TH, Ip NY, Stahl N, Scherer S, Farruggella T, DiStefano PS, Curtis R, Panayotatos N, Gascan H, et al.. Released form of CNTF receptor alpha component as a soluble mediator of CNTF responses. Science. 1993 Mar 19;259(5102):1736-9. PMID:7681218
  5. ↑ 5.0 5.1 Schuster B, Kovaleva M, Sun Y, Regenhard P, Matthews V, Grotzinger J, Rose-John S, Kallen KJ. Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF. J Biol Chem. 2003 Mar 14;278(11):9528-35. PMID:12643274
  6. ↑ 6.0 6.1 6.2 6.3 Cognet I, Guilhot F, Chevalier S, Guay-Giroux A, Bert A, Elson GC, Gascan H, Gauchat JF. Expression of biologically active mouse ciliary neutrophic factor (CNTF) and soluble CNTFRalpha in Escherichia coli and characterization of their functional specificities. Eur Cytokine Netw. 2004 Jul-Sep;15(3):255-62. PMID:15542451
  7. ↑ 7.0 7.1 7.2 7.3 Sleeman MW, Anderson KD, Lambert PD, Yancopoulos GD and Wiegand SJ. "The ciliary neurotrophic factor and its receptor, CNTFRα". Pharm Acta Helv 74: 265-272 (2000). http://dx.doi.org/10.1016/S0165-7208(00)80028-8
  8. ↑ Takahashi R, Yokoji H, Misawa H, Hayashi M, Hu J, Deguchi T. A null mutation in the human CNTF gene is not causally related to neurological diseases. Nat Genet. 1994 May;7(1):79-84. PMID:8075647 doi:http://dx.doi.org/10.1038/ng0594-79
  9. ↑ Giess R, Maurer M, Linker R, Gold R, Warmuth-Metz M, Toyka KV, Sendtner M, Rieckmann P. Association of a null mutation in the CNTF gene with early onset of multiple sclerosis. Arch Neurol. 2002 Mar;59(3):407-9. PMID:11890844
  10. ↑ Dutta R, McDonough J, Chang A, Swamy L, Siu A, Kidd GJ, Rudick R, Mirnics K, Trapp BD. Activation of the ciliary neurotrophic factor (CNTF) signalling pathway in cortical neurons of multiple sclerosis patients. Brain. 2007 Oct;130(Pt 10):2566-76. PMID:17898009 doi:http://dx.doi.org/10.1093/brain/awm206
  11. ↑ Li Y, Tao W, Luo L, Huang D, Kauper K, Stabila P, Lavail MM, Laties AM, Wen R. CNTF induces regeneration of cone outer segments in a rat model of retinal degeneration. PLoS One. 2010 Mar 2;5(3):e9495. doi: 10.1371/journal.pone.0009495. PMID:20209167 doi:http://dx.doi.org/10.1371/journal.pone.0009495
  12. ↑ Sieving PA, Caruso RC, Tao W, Coleman HR, Thompson DJ, Fullmer KR, Bush RA. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3896-901. Epub 2006 Feb 27. PMID:16505355 doi:http://dx.doi.org/10.1073/pnas.0600236103
  13. ↑ Talcott KE, Ratnam K, Sundquist SM, Lucero AS, Lujan BJ, Tao W, Porco TC, Roorda A, Duncan JL. Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment. Invest Ophthalmol Vis Sci. 2011 Apr 6;52(5):2219-26. doi: 10.1167/iovs.10-6479. PMID:21087953 doi:http://dx.doi.org/10.1167/iovs.10-6479
  14. ↑ Ettinger MP, Littlejohn TW, Schwartz SL, Weiss SR, McIlwain HH, Heymsfield SB, Bray GA, Roberts WG, Heyman ER, Stambler N, Heshka S, Vicary C, Guler HP. Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study. JAMA. 2003 Apr 9;289(14):1826-32. PMID:12684362 doi:http://dx.doi.org/10.1001/jama.289.14.1826
  15. ↑ 15.0 15.1 McDonald NQ, Panayotatos N, Hendrickson WA. Crystal structure of dimeric human ciliary neurotrophic factor determined by MAD phasing. EMBO J. 1995 Jun 15;14(12):2689-99. PMID:7796798
  16. ↑ Panayotatos N, Radziejewska E, Acheson A, Somogyi R, Thadani A, Hendrickson WA, McDonald NQ. Localization of functional receptor epitopes on the structure of ciliary neurotrophic factor indicates a conserved, function-related epitope topography among helical cytokines. J Biol Chem. 1995 Jun 9;270(23):14007-14. PMID:7539796
  17. ↑ Kallen KJ, Grotzinger J, Lelievre E, Vollmer P, Aasland D, Renne C, Mullberg J, Myer zum Buschenfelde KH, Gascan H, Rose-John S. Receptor recognition sites of cytokines are organized as exchangeable modules. Transfer of the leukemia inhibitory factor receptor-binding site from ciliary neurotrophic factor to interleukin-6. J Biol Chem. 1999 Apr 23;274(17):11859-67. PMID:10207005
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